Hematology Pharmacology

Front 1

How would you manage Heparin induced thrombocytopenia?

Back 1

Stop the heparin

Front 2

What are the paradoxes associated with HIT?

Back 2

Treat with blood thinner yet see blood clots
Lowered platelet count, expect bleeding disorder but still clotting disorder.
Simply stopping Heparin may not prevent blood clots
Platelets transfusions can worsen thrombosis
Do not switch to warfarin, as acute monotherapy

Front 3

Activated platelets release this protein that binds to heparin

Back 3

Platelet Factor 4 (PF4)

Front 4

What is the initiation event in Heparin induced thrombocytopenia ?

Back 4

Heparin-PF4 complex is seen as foreign by the body which then is bound by IgG. The Fc receptor binds more platelets and activates them and this is the start of a viscious cycle.

Front 5

How are blood cells targeted for injury in a patient with Heparin induced thrombocytopenia?

Back 5

The blood vessels have heparin-like molecules which bind to PF4, as it is being released in large amounts. IgG bind the complex and downstream of this is the injury of the blood vessels. Injured blood vessels + activated platelets --> recipie for disaster.

Front 6

Why is HIT considered a thrombotic disease?

Back 6

Thrombin amplifies and perpetuates HIT via the following:
Thrombin activates endothelial cells --> form cytokines and Tissue Factor
Thrombin activates monocytes --> form cytokines and Tissue Factor.
Thrombin activates platelets --> Platelet aggregation, release of granules & TXA2 synthesis. Activated platelets cause th release of more thrombin.
Thrombin activates the coagulation cascade:
Fibrinogen - Fibrin
Factor XIII - XIIIa
Amplification:
Factor VIII - VIIIa
Factor V - Va
Protein C

Front 7

Where does Heparin come from?

Back 7

Natural source: cow, lung, porcein intestine, heterogenous product that is sulfated. It is a polymer of variety of different lengths.

Front 8

What patients/ clinical setting are patients more likely to get HIT?

Back 8

Cardiac
Orthopedic
Intensive care

Front 9

Name a clotting disorder in which can get clots in either venous or arteries

Back 9

HIT

Front 10

Clinical sequelae of HIT:

Back 10

Another thrombus - 50%
Amputation - 21%
Death - 30%MI, stroke, occlusion of vital organ, primary embolus

Front 11

What is the typical time period for the onset of HIT?

Back 11

4 - 14 days, 90% of cases that occur.

Front 12

Why might one have a rapid onset of HIT?

Back 12

Previous exposure to Heparin.

Front 13

Why might one have a delayed onset of HIT?

Back 13

9 - 10 days after heparin stopped still have antibodies that are bound to heparin-like molecules on endothelial cells.

Front 14

How do you diagnose HIT?

Back 14

Fall of platelet count with the right timing with respect to starting the heparin <150,000.
Drop of platelets 30 - 50% from baseline even though not in the thrombocytopenic range, stressed people may have high amounts of platelets.
DO NOT DELAY TREATMENT, INITIATE RX BEFORE GETTING LABORATORY TEST BACK. THIS IS A CLINICAL Dx, LAB HELPS CONFIRM DIAGNOSIS.

Front 15

Differential dx of thrombocytopenia in ICU?

Back 15

Severe sepsis, DIC
Drugs - lower platelet count
Dilutional effect - due to blood transfusion
If have had blood go through extracorporeal circuit

Front 16

What lab tests would you order to diagnose HIT?

Back 16

Draw blood sample
Test antibody presence
ELISA test against Heparin and PF4
Test ab ability to activate platelets - load up platelets with radioactive serotonin and measure how much serotonin comes out.

Front 17

Which test is the gold standard for diagnosis of HIT because of its specificity?

Back 17

SRA (Serotonin Release Assay) -has 100% specificity. If positive, then can be certain that these antibodies are specific for HIT.
ELISA test - sensitive - used for its negative predictive value.

Front 18

What kind of thrombocytopenia does this patient have? 50 - 150 0000

Back 18

Mild thrombocytopenia

Front 19

What kind of thrombocytopenia does this patient have? 20 -50,000

*** MAJORITY OF HIT PATIENTS ***

Back 19

mild - moderate thrombocytopenia

Front 20

What kind of thrombocytopenia does this patient have? <20,000

Back 20

severe thrombocytopenia

Front 21

How do you treat HIT?

Back 21

CLINICAL SUSPISCION OR DIAGNOSIS OF HIT --> STOP ALL FORMS OF HEPARIN IMMEDIATMO --> STRONGLY CONSIDER ANTICOAGULATION W/ DTI (DIRECT THROMBIN INHIBITORS)--> CONFIRMATORY TESTS.

Front 22

Name two bivalent DTI's that bind and block both the fibrinogen binding site and active site:

Back 22

Bivalirudin
Lepirudin

Front 23

DTI that blocks the active binding site only:

Back 23

Argatroban

Front 24

Name this drug is the recombinant for of Hirudin - an anticoagulant from saliva of leeches and was first drug approved for HIT:

Back 24

Lepirudin

Front 25

Half life of Lepirudin.
How is it excreted?

Back 25

Excreted via kidney
Half life is 80 minutes, to have constant drug in the body with short half life, would give a continuous IV.

Front 26

This drug is active site specific, indicated in prophylaxis and Rx of HIT, does not cross-react with heparin induced ab.

Back 26

Argatroban

Front 27

How is Argatroban eliminated?
Half life:

Back 27

Liver
39-51 minutes.

Front 28

Which drug needs care when switching over with coumadin (oral anticoagulant) because even though monitored with aPTT it can still affect the INR:
*** MUI IMPORTANTE ***

Back 28

Argatroban.
Lepirudin has little effect on INR (Both drugs are monitored looking at aPTT)

Front 29

Which anticoagulants are not to be used in HIT and why?

Back 29

Warfarin - don't use as monotherapy
LMWH - May crossreact with heparin antibodies.

Front 30

When, if ever, can a patient with a hx of HIT, be re-exposed to heparin?

Back 30

Ab negative
Remote hx of HIT
No comparative txt
Ltd exposure to heparin

Front 31

What is the active component that breaks down clots?

Back 31

Plasminogen --> activated to --> Plasmin

Front 32

What are the targets of plasmin

Back 32

Fibrin
Factor V
Factor VIII

Front 33

How can you block activation of plasminogen?

Back 33

alpha-2anti-plasmin - blocks active enzyme
Plasminogen activator inhibitor - block conversion to active enzyme

Front 34

Name two plasminogen activators found in our bodies:

Back 34

tpa - Tissue plasminogen activator
Urokinase plasminogen activator

Front 35

Name two plasminogen activators available therapeutically:

Back 35

Streptokinase - not used though because tends to be immunogenic
Contact system

Front 36

Main disadvantage of clot busters?

Back 36

If given systemically, likely to cause hemorrhage.

Front 37

What is the rationale for the use of anticoagulant medications:

Back 37

Prevent propagation of clots (Rx)
Prevent formation of new clots (prophylaxis)
Prevent formation of recurrent clots (secondary prophylaxis)

Front 38

Heparin:
What is the MOA?
How is it eliminated?
Half life?
How would you reverse the effects of heparin?
How is Heparin monitored?

Back 38

Binds to antithrombin III --> inhibit factors Xa and IIa

Eliminated via the reticuloendothelial system.
Heparin is monitored by measuring the aPTT - intrinsic pathway.
Has a half life of 1 - 1.5hrs
Reverse effects by administering protamine sulfate

Front 39

List four LMWH drugs - generic names:

Back 39

Enoxaparin
Dalteparin
Tinzaparin
Fondaparinux - longer half life than the others = 17 - 21hrs

Front 40

LMWH:
hat is the MOA?
How is it eliminated?
Half life?
How would you reverse the effects of heparin?
How is LMWH monitored?

Back 40

MOA: Antithrombin III - inhibit Xa and IIa
Elimination: RENAL ***
Half life = 2.5 - 4.5hrs
Reverse = ONLY 60% REVERSAL IS ACHIEVED WITH PROTAMINE SULFATE, except Fondaparinux has no reversal agent at this time.
Monitoring: No monitoring is necessary

Front 41

Difference between the route of administration of heparin vs that of LMWH:

Back 41

Heparin is administered IV whereas LMWH is given subcutaneously.

Front 42

Warfarin:
What is the MOA?

Back 42

MOA: Inactivates Vitamin K Reductase. Hence do not have the reduced form of vitamin K that is needed for carboxylation o glutamic acid residues to form gamma carboxylation of ***Factors II, VII, IX, X, protein C and protein S ***

Front 43

Warfarin:
How is it eliminated?
Half life?
How would you reverse the effects of warfarin?
How is warfarin monitored?

Back 43

Elimination: Hepatic metabolism and unleashed via urine and stool. ALWAYS THINK OF DRUG INTERACTIONS WITH WARFARIN.
Half life: 40hrs
Reverse effects: Vitamin K, Fresh Frozen plasma, Profilnine
Monitored: INR

Front 44

How long does it take for all coagulation factors (II, VII, IX and X) to be inhibited by warfarin?

Back 44

5 days, patients are given warfarin as prophylaxis and prevention of recurrent clots. For the first five days, they will be on both heparin and warfarin until the effect of warfarin kicks in.

Front 45

Name some of the clinical applications of anticoagulant medications:

Back 45

Prevent DVT and PE after surgery
Prevent DVT and PE in hospitalized medically ill patients
Treat acute DVT or PE
Treat Embolic stroke
Treat atrial fibrillation
Treat patients with mechanical prosthetic hearts
Acute coronary syndrome

Front 46

Describe HIT Type 1 syndrome:

Back 46

Heparin associated thrombocytopenia which is transient, mild, non-immunologic and occurs within 4 days of exposure. It is rapidly reversible and asymptomatic.

Front 47

Why is the use of warfarin monotherapy without a systemic anticoagulant contraindicated?

Back 47

Warfarin on its own may exacerbate venous gangrene

Front 48

What is the aim of laboratory diagnosis in Rx of HIT?

Back 48

Need tests that can determine the antibody responsible for platelet activation and aggregation.

Front 49

How is the Serotonin Release
Assay test performed in Dx of HIT?

Back 49

Patients serum is mixed with donor platelets that were incubated with radioactive serotonin. Normally, serotonin is released by activated platelets in presence of heparin

Front 50

What is the major disadvantage of Heparin alternative drugs that may be used in HIT patients?

Back 50

They do not have reversal agents if bleeding was to occur.

Front 51

What are the indications for use of thrombolytic therapy?

Back 51

MI within 6hrs
Peripheral arterial or graft occlusion ( usually by catheter delivery)
Cerebrovascular accident if given within 3hrs of first symptoms
PE
DVT

Front 52

Contraindications for thromboembolytic therapy use:

Back 52

Surgery within 10 days
Trauma within 10 days
Serious GI bleed within the past 3 months
Hx of htn
Active bleed or hemorrhagic disorder.
Previous cerebrovascular or intravascular process
Aortic dissection
Acute pericarditis

Front 53

TRUE OR FALSE
All thromboembolytic drugs require follow up treatment with an antithrombotic or anticoagulant agent.

Back 53

TRUE